The present invention relates to compounds useful for raising cellular ABCA-1 production in mammals, and to methods of using such compounds in the treatment of coronary artery diseases. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.
Cholesterol is essential for the growth and viability of higher organisms. It is a lipid that modulates the fluidity of eukaryotic membranes, and is the precursor to steroid hormones such as progesterone, testosterone, and the like. Cholesterol can be obtained from the diet, or synthesized internally in the liver and the intestines. Cholesterol is transported in body fluids to specific targets by lipoproteins, which are classified according to increasing density. For example, low density lipoprotein cholesterol (LDL) is responsible for transport of cholesterol to and from the liver and to peripheral tissue cells, where LDL receptors bind LDL, and mediate its entry into the cell.
Although cholesterol is essential to many biological processes in mammals, elevated serum levels of LDL cholesterol are undesirable, in that they are known to contribute to the formation of atherosclerotic plaques in arteries throughout the body, which may lead, for example, to the development of coronary artery diseases. Conversely, elevated levels of high density lipoprotein cholesterol (HDL-C) have been found, based upon human clinical data, and animal model systems, to protect against development of coronary diseases.
In general, excess cholesterol is removed from the body by a pathway involving high density lipoproteins (HDLs). Cholesterol is xe2x80x9ceffluxedxe2x80x9d from cells by one of two processesxe2x80x94either by passive transfer to mature HDL, or an active transfer to apolipoprotein A-1. The latter process is mediated by a protein known as ATP binding cassette transporter 1 (ABC-1, or alternatively referenced as ABCA-1). In the latter process, lipid-poor HDL precursors acquire phospholipid and cholesterol, which leads to increased plasma levels of mature HDL particles. HDL cholesterol is eventually transported to the liver in a process known as xe2x80x9creverse cholesterol transportxe2x80x9d, where it is either recycled or excreted as bile.
One method of treatment aimed at reducing the risk of formation of atherosclerotic plaques in arteries relates to decreasing plasma lipid levels. Such a method includes diet changes, and/or treatment with drugs such as derivatives of fibric acid (clofibrate, gemfibrozil, and fenofibrate), nicotinic acid, and HMG-CoA reductase inhibitors, such as mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, and lovastatin, which reduce plasma LDL cholesterol levels by either inhibiting the intracellular synthesis of cholesterol or inhibiting the uptake via LDL receptors. In addition, bile acid-binding resins, such as cholestyrine, colestipol and probucol decrease the level of LDL-cholesterol by reducing intestinal uptake and increasing the catabolism of LDL-cholesterol in the liver.
It is desired to provide alternative therapies aimed at reducing the risk of formation of atherosclerotic plaques in arteries, especially in individuals deficient in the removal of cholesterol from artery walls via the HDL pathway. Given that HDL levels are generally related to the expression of ABCA-1, one method of increasing HDL levels would be to increase the expression of ABCA-1. Accordingly, it is desired to provide compounds that are potent stimulators of the expression of ABCA-1 in mammals, thus increasing cholesterol efflux and raising HDL cholesterol levels in blood. This would be useful for the treatment of various disease states characterized by low HDL levels, in particular coronary artery disease.
It has also been shown that a combination of a drug that decreases LDL cholesterol levels and a drug that increases HDL cholesterol is beneficial; see, for example, Arterioscler., Thromn., Vasc. Biol. (2001), 21(8), 1320-1326, by Marian C. Cheung et al. Accordingly, it is also desired to provide a combination of a compound that stimulates the expression of ABCA-1 with a compound that lowers LDL cholesterol levels.
It should be noted it has also been shown that raising ABCA-1 production in macrophages locally reduces cholesterol deposition in coronary arteries without significantly raising plasma HDL cholesterol. In this instance, raising ABCA-1 expression is beneficial even in the absence of increased HDL cholesterol.
Accordingly, it is an object of this invention to provide compounds that elevate cellular expression of the ABCA-1 gene in a mammal. Accordingly, in a first aspect, the invention relates to compounds of Formula I useful for increasing ABCA-1 expression:
R1xe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94NR2R3xe2x80x83xe2x80x83Formula I 
wherein:
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R2 and R3 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or
R2 and R3 when taken together with the nitrogen atom to which they are attached form a heterocyclic moiety;
X is oxygen, sulfur, or xe2x80x94NR4xe2x80x94;
Y is optionally substituted alkylene or a covalent bond;
wherein R4 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, xe2x80x94S(O)2R5, xe2x80x94C(O)R5, or xe2x80x94C(O)NHR5, in which R5 is optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
Z is xe2x80x94C(O)xe2x80x94Z1xe2x80x94, xe2x80x94C(S)xe2x80x94Z1xe2x80x94, or xe2x80x94SO2xe2x80x94Z1xe2x80x94;
in which Z1 is lower alkylene or a covalent bond, with the proviso that when R1, R2, or R3 is alkenyl or alkynyl, the double bond of the alkenyl or the triple bond of the alkynyl is located at least two carbon atoms away from the attachment to the nitrogen.
In a second aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be usefully treated with a compound that elevates serum levels of HDL cholesterol, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease.
In a third aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be usefully treated with a compound that promotes cholesterol efflux from cells, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease.
In a fourth aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a disease or condition characterized by low HDL cholesterol in a mammal that can be usefully treated with a compound that elevates serum levels of HDL cholesterol, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease, and diabetes.
In a fifth aspect, the invention relates to a method for using the compounds of Formula I in the treatment of a condition related to coronary artery disease in a mammal that can be usefully treated with a combination of a compound that elevates serum levels of HDL cholesterol and a compound that lowers LDL cholesterol, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I and a compound that lowers LDL cholesterol.
A sixth aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one pharmaceutically acceptable excipient.
A seventh aspect of this invention relates to methods of preparing the compounds of Formula I.
Definitions and General Parameters
The term xe2x80x9calkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to:
1) an alkyl group as defined above, having from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
2) an alkyl group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and xe2x80x94NRaxe2x80x94, where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
3) an alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term xe2x80x9clower alkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.
The term xe2x80x9csubstituted lower alkylxe2x80x9d refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1 to 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1-5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms as defined above.
The term xe2x80x9calkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.
The term xe2x80x9clower alkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 6 carbon atoms.
The term xe2x80x9csubstituted alkylenexe2x80x9d refers to:
(1) an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or
(2) an alkylene group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and NRaxe2x80x94, where Ra is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or
(3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of substituted alkylenes are chloromethylene (xe2x80x94CH(Cl)xe2x80x94), aminoethylene (xe2x80x94CH(NH2)CH2xe2x80x94), methylaminoethylene (xe2x80x94CH(NHMe)CH2xe2x80x94), 2-carboxypropylene isomers(xe2x80x94CH2CH(CO2H)CH2xe2x80x94), ethoxyethyl (xe2x80x94CH2CH2Oxe2x80x94CH2CH2xe2x80x94), ethylmethylaminoethyl (xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94),1-ethoxy-2-(2-ethoxy-ethoxy)ethane (xe2x80x94CH2CH2Oxe2x80x94CH2CH2xe2x80x94OCH2CH2xe2x80x94OCH2CH2xe2x80x94), and the like.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. xe2x80x9cOptionally substituted aralkylxe2x80x9d refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x94Oxe2x80x94, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group xe2x80x94Yxe2x80x94Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy groups are optionally substituted alkyl-Oxe2x80x94 and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.
The term xe2x80x9calkylthioxe2x80x9d refers to the group Rxe2x80x94Sxe2x80x94, where R is as defined for alkoxy.
The term xe2x80x9calkenylxe2x80x9d refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl). Preferred alkenyl groups include ethenyl or vinyl (xe2x80x94CHxe2x95x90CH2), 1-propylene or allyl (xe2x80x94CH2CHxe2x95x90CH2), isopropylene (xe2x80x94C(CH3)xe2x95x90CH2), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to nitrogen, the double bond cannot be alpha to the nitrogen.
The term xe2x80x9clower alkenylxe2x80x9d refers to alkenyl as defined above having from 2 to 6 carbon atoms.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamnino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9calkynylxe2x80x9d refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (xe2x80x94Cxe2x89xa1xe2x80x94CH), propargyl (or prop-1-yn-3-yl, xe2x80x94CH2Cxe2x89xa1CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9caminocarbonylxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9cacylaminoxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9cacyloxyxe2x80x9d refers to the groups xe2x80x94O(O)C-alkyl, xe2x80x94O(O)C-cycloalkyl, xe2x80x94O(O)C-aryl, xe2x80x94O(O)C-heteroaryl, and xe2x80x94O(O)C-heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9carylxe2x80x9d refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9caryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term xe2x80x9carylthioxe2x80x9d refers to the group Rxe2x80x94Sxe2x80x94, where R is as defined for aryl.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to the group xe2x80x94NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group xe2x80x94Yxe2x80x94Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl, All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9ccarboxyalkylxe2x80x9d refers to the groups xe2x80x94C(O)O-alkyl, xe2x80x94C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, noradamantyl, bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or cyclic alkyl groups to which is fused an aryl group, for example indan, and the like.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluoro, bromo, chloro, and iodo.
The term xe2x80x9cacylxe2x80x9d denotes a group xe2x80x94C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic group (i.e., unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl). Examples of heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogen containing heteroaryl compounds.
The term xe2x80x9cheteroaralkylxe2x80x9d refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein. xe2x80x9cOptionally substituted heteroaralkylxe2x80x9d refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group. Such heteroaralkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.
The term xe2x80x9cheteroaryloxyxe2x80x9d refers to the group heteroaryl-Oxe2x80x94.
The term xe2x80x9cheterocyclylxe2x80x9d refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, SO2-aryl and xe2x80x94SO2-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or xe2x80x94S(O)nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.
The term xe2x80x9cthiolxe2x80x9d refers to the group xe2x80x94SH.
The term xe2x80x9csubstituted alkylthioxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
The term xe2x80x9cheteroarylthiolxe2x80x9d refers to the group xe2x80x94S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
The term xe2x80x9csulfoxidexe2x80x9d refers to a group xe2x80x94S(O)R, in which R is alkyl, aryl, or heteroaryl. xe2x80x9cSubstituted sulfoxidexe2x80x9d refers to a group xe2x80x94S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term xe2x80x9csulfonexe2x80x9d refers to a group xe2x80x94S(O)2R, in which R is alkyl, aryl, or heteroaryl. xe2x80x9cSubstituted sulfonexe2x80x9d refers to a group xe2x80x94S(O)2R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term xe2x80x9cketoxe2x80x9d refers to a group xe2x80x94C(O)xe2x80x94. The term xe2x80x9cthiocarbonylxe2x80x9d refers to a group xe2x80x94C(S)xe2x80x94. The term xe2x80x9ccarboxyxe2x80x9d refers to a group xe2x80x94C(O)xe2x80x94OH.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
The term xe2x80x9ccompound of Formula Ixe2x80x9d is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, and prodrugs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
xe2x80x9cIsomersxe2x80x9d are different compounds that have the same molecular formula.
xe2x80x9cStereoisomersxe2x80x9d are isomers that differ only in the way the atoms are arranged in space.
xe2x80x9cEnantiomersxe2x80x9d are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a xe2x80x9cracemicxe2x80x9d mixture. The term xe2x80x9c(xc2x1)xe2x80x9d is used to designate a racemic mixture where appropriate.
xe2x80x9cDiastereoisomersxe2x80x9d are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog Rxe2x80x94S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (xe2x88x92) depending on the direction (dextro-or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The term xe2x80x9ccoronary artery diseasexe2x80x9d means a chronic disease in which there is a xe2x80x9chardeningxe2x80x9d (atherosclerois) of the coronary arteries.
The term xe2x80x9catherosclerosisxe2x80x9d refers to a form of arteriosclerosis in which deposits of yellowish plaques containing cholesterol, lipoid material, and lipophages are formed within the intima and inner media of large and medium-sized arteries.
The term xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any treatment of a disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or
(iii) relieving the disease, that is, causing the regression of clinical symptoms.
In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
As used herein, xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
Nomenclature
The naming of the compounds of the invention is illustrated with a representative compound of Formula I in which R1 is 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl, R2 is cyclohexyl, R3 is phenyl, X is NR4, in which R4 is hydrogen, Y is methylene, and Z is xe2x80x94C(O)xe2x80x94. 
which is named: 2-(1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamino)N-cyclohexyl-N-phenylacetamide.
Synthetic Reaction Parameters
The terms xe2x80x9csolventxe2x80x9d, xe2x80x9cinert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), dimethylformamide (xe2x80x9cDMFxe2x80x9d), chloroform, methylene chloride (or dichloromethane, DCM), diethyl ether, methanol, pyridine and the like]. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents.
The term xe2x80x9cq.s.xe2x80x9d means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
Synthesis of the Compounds of Formula I
A method for preparing the compounds of Formula I where X is xe2x80x94NR4xe2x80x94 and Z is xe2x80x94C(O)xe2x80x94 is shown in Reaction Scheme I. 
where Y is optionally substituted alkylene
Preparation of Formula I
The compound of formula (1) is either commercially available or prepared by means well known in the art. The compound of formula (1) is reacted with an amine of the formula R1TNHR4 in a protic solvent, for example isopropanol, in the presence of a tertiary base, for example triethylamine, at a temperature of between about 25xc2x0 to 100xc2x0 C., for about 8 to 48 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
An example of the preparation of a compound of formula (1) is shown below: 
The compound of formula R2R3NH is reacted with chloroacetyl chloride in the presence of a base, preferably sodium carbonate. The reaction is carried out in an inert solvent, preferably diethyl ether, at a temperature of about 0-30xc2x0 C., for about 4-24 hours. When the reaction is substantially complete, the product of formula (1) is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Synthesis of the Compounds of Formula I
A method for preparing the compounds of Formula I where X is xe2x80x94NR4xe2x80x94 and Z is xe2x80x94C(O)CH2xe2x80x94 is shown in Reaction Scheme II. 
The compound of formula (2) is prepared in a manner analogous to that shown above for the compound of formula (1), by reaction of an amine of formula R1NR4H with chloroacetyl chloride.
The compound of formula (2) is then reacted with an amine of formula R2R3NH in the same manner as shown above in Reaction Scheme I, i.e., in a protic solvent, for example isopropanol, in the presence of a tertiary base, for example triethylamine.
Synthesis of the Compounds of Formula I
Compounds of Formula I where X is xe2x80x94NR4xe2x80x94, Y is a covalent bond, and Z is xe2x80x94C(S)xe2x80x94 or xe2x80x94C(S)CH2xe2x80x94 may be prepared by reacting the compounds of Formula I in which X is xe2x80x94NR4xe2x80x94, Y is a covalent bond, and Z is xe2x80x94C(O)xe2x80x94 or xe2x80x94C(O)CH2xe2x80x94 with Lawesson""s reagent. The reaction is carried out in an inert solvent, for example chlorobenzene, at a temperature of about 80xc2x0 to 120xc2x0 C., for about 30 minutes to 6 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Synthesis of the Compounds of Formula I
To prepare compounds of Formula I where X is xe2x80x94NR4xe2x80x94, in which R4 is xe2x80x94C(X1)NHR5, where X1 is sulfur or oxygen, the compounds of Formula I in which R4 is hydrogen are reacted with an isocyanate or isothiocyanate, as shown in Reaction Scheme III. 
The compound of Formula I in which R4 is hydrogen is reacted with an isocyanate or isothiocyanate of formula R5NCX1, where X1 is oxygen or sulfur, in the presence of a catalytic amount of 4-dimethylaminopyridine (DMAP), and a tertiary base, preferably triethylamine. The reaction is carried out in an inert solvent, for example acetonitrile, at a temperature of about 0-30xc2x0 C., preferably about room temperature, for about 4-24 hours. When the reaction is substantially complete, the product of Formula I in which R4 is R5NHC(X1)xe2x80x94 is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Synthesis of the Compounds of Formula I
To prepare compounds of Formula I where X is xe2x80x94NR4xe2x80x94, in which R4 is xe2x80x94C(X1)R5, where X1 is sulfur or oxygen, the compounds of Formula I in which R4 is hydrogen are reacted with a compound of formula R5C(X1)Cl, as shown in Reaction Scheme IV. 
The compound of Formula I in which R4 is hydrogen is initially reacted with a strong base, preferably sodium hydride. The reaction is carried out in an inert solvent, preferably tetrahydrofuran, at a temperature of about 0xc2x0 C., for about 1-30 minutes. After this, a compound of formula R5C(X1)Cl, where X1 is oxygen or sulfur, is added, and the mixture allowed to warm to about room temperature for about 8-24 hours. When the reaction is substantially complete, the product of Formula I in which R4 is R5C(X1)xe2x80x94 is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Synthesis of the Compounds of Formula I
A method of preparing compounds of Formula I in which X is xe2x80x94NHxe2x80x94, Y is a covalent bond, and Z is xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 is shown in Reaction Scheme V. 
The amine of formula R2R3NH is reacted with an isocyanate or isothiocyanate of formula R1NCX, where X is oxygen or sulfur, in the presence of a catalytic amount of 4-dimethylaminopyridine (DMAP). The reaction is carried out in an inert solvent, for example acetonitrile, at a temperature of about 0-30xc2x0 C., preferably about room temperature, for about 4-24 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Synthesis of the Compounds of Formula I
A method for preparing the compounds of Formula I where X is oxygen or sulfur is shown in Reaction Scheme VI. 
The compound of formula R1XH, where X is oxygen or sulfur (for example, a phenol or thiophenol) is reacted with the compound of formula (1) in the presence of a strong inorganic base, for example sodium hydroxide or potassium hydroxide. The reaction is carried out in an inert solvent, for example tetrahydrofuran, at a temperature of about 0-30xc2x0 C., preferably about room temperature, for about 4-24 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
To prepare similar compounds where R1 is not an aromatic group, for example where R1 is alkyl or cycloalkyl, the reaction is carried out similarly, but using sodium hydride to form the anion, or where X is xe2x80x94NHxe2x80x94, the reaction is carried out in a protic solvent, preferably isopropanol, in the presence of a tertiary base, preferably triethylamine.
Synthesis of the Compounds of Formula I
A method for preparing the compounds of Formula I where X is xe2x80x94NR4xe2x80x94, in which R4 is xe2x80x94SO2R5 is shown in Reaction Scheme VII. 
The compound of Formula I in which R4 is hydrogen is reacted with a sulfonyl chloride of the formula R5SO2Cl. The reaction is carried out in an inert solvent, for example methylene chloride in the presence of a tertiary base, preferably triethylamine, at a temperature of about 0-30xc2x0 C., preferably about room temperature, for about 8-24 hours. When the reaction is substantially complete, the product of Formula I in which R4 is R5SO2xe2x80x94 is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
Synthesis of the Compounds of Formula I
A method for preparing the compounds of Formula I where X is xe2x80x94NR4xe2x80x94, in which R4 is optionally substituted alkyl is shown in Reaction Scheme VII. 
The compound of Formula I in which R4 is optionally substituted alkyl is prepared from the compound of Formula I in which R4 is hydrogen by a conventional reductive amination procedure. For example, reaction with formaldehyde/sodium cyanoborohydride provides a compound of Formula I in which R4 is methyl. Reaction with benzaldehyde/sodium cyanoborohydride provides a compound of Formula I in which R4 is benzyl (i.e., methyl substituted by phenyl). The reaction is carried out in an inert solvent, for example acetonitrile, at a pH of about 2, at a temperature of about 0-30xc2x0 C., preferably about room temperature, for about 8-24 hours. When the reaction is substantially complete, the product of Formula I in which R4 is optionally substituted alkyl is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.
General Utility
The compounds of Formula I stimulate the expression of ABCA-1 in mammalian cells, thus increasing cholesterol efflux and raising HDL levels in plasma. Therefore, the compounds of Formula I are useful for treating conditions related to high cholesterol/low HDL levels in mammals, including, but not limited to, coronary artery disease, including that produced by diabetes, and the like.
Testing
Activity testing is conducted as described in those patents and patent applications referenced above, and in the Examples below, and by methods apparent to one skilled in the art.
Pharmaceutical Compositions
The compounds of Formula I are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The compounds of Formula I may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington""s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and xe2x80x9cModem Pharmaceuticsxe2x80x9d, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. T. Rhodes, Eds.).
Administration
The compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
One mode for administration is parental, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of Formula I in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral administration is another route for administration of the compounds of Formula I. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound of Formula I, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (xe2x80x9cpatchesxe2x80x9d). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
The compositions are preferably formulated in a unit dosage form. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds of Formula I are effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 10 mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of a compound of Formula I, more preferably about 50-200 mg. It will be understood, however, that the amount of the compound of Formula I actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.